Introduction

Background

Chronic obstructive pulmonary disease (COPD) is a disorder that causes a huge degree of human suffering. According to the US Centers for Disease Control and Prevention (CDC), COPD is currently the fourth leading cause of death in the United States.

In Western Europe, Badham (1808) and Laennec (1827) made the classic description of chronic bronchitis and emphysema in the early 19th century. A British medical textbook of the 1860s described the familiar clinical picture of chronic bronchitis as an advanced disease with repeated bronchial infections that ended in right-sided heart failure. Overall, this malady caused more than 5% of all deaths in the Middle Ages and earlier. The condition was the most common among the poor; therefore, it was attributed to "bad" living.

Developments in the 20th century include the widespread use of spirometry, recognition of airflow obstruction as a key factor in determining disability, and the improvement of pathological methods to assess emphysema. Participants of the Ciba symposium of 1958 proposed definitions of chronic bronchitis and emphysema, incorporating the concept of airflow obstruction.

Chronic bronchitis is defined clinically as the presence of a chronic productive cough for 3 months during each of 2 consecutive years (other causes of cough being excluded). Emphysema, on the other hand, is defined pathologically as an abnormal, permanent enlargement of the air spaces distal to the terminal bronchioles, accompanied by destruction of their walls and without obvious fibrosis. Airflow limitation in emphysema is due to loss of elastic recoil and decrease in airway tethering, whereas chronic bronchitis leads to narrowing of airway caliber and increase in airway resistance. Although some patients predominantly display signs of one or the other, most fall somewhere in the middle of the spectrum.

The past definitions of COPD have been pessimistic at best, suggesting that the disease process is irreversible with little therapy to offer. More recently, however, a more optimistic definition has become widely accepted. The Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines define COPD as a disease state characterized by airflow limitation that is not fully reversible, is usually progressive, and is associated with an abnormal inflammatory response of the lungs to inhaled noxious particles or gases.¹ This definition shifts the paradigm of the disease, suggesting that it is both treatable and preventable. For a guideline summary, see Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease.² 

Venn diagram of chronic obstructive pulmonary disease (COPD). Chronic obstructive lung disease is a disorder in which subsets of patients may have dominant features of chronic bronchitis, emphysema, or asthma. The result is irreversible airflow obstruction.

Additionally, the Medscape COPD Resource Center may be helpful.

Pathophysiology

Pathological changes in chronic obstructive pulmonary disease (COPD) occur in the large (central) airways, the small (peripheral) bronchioles, and the lung parenchyma. The pathogenic mechanisms are not clear but most likely involve diverse mechanisms. The increased number of activated polymorphonuclear leukocytes and macrophages release elastases in a manner that cannot be counteracted effectively by antiproteases, resulting in lung destruction. The primary offender has been human leukocyte elastase, with a possible synergistic role suggested for proteinase 3 and macrophage-derived matrix proteinases, cysteine proteinases, and a plasminogen activator. Additionally, increased oxidative stress caused by free radicals in cigarette smoke, the oxidants released by phagocytes, and polymorphonuclear leukocytes all may lead to apoptosis or necrosis of exposed cells. Accelerated aging and autoimmune mechanisms have also been proposed as having roles in the pathogenesis of COPD.^3,4 

Chronic bronchitis

Mucous gland enlargement is the histologic hallmark of chronic bronchitis. The structural changes described in the airways include atrophy, focal squamous metaplasia, ciliary abnormalities, variable amounts of airway smooth muscle hyperplasia, inflammation, and bronchial wall thickening. Neutrophilia develops in the airway lumen, and neutrophilic infiltrates accumulate in the submucosa. The respiratory bronchioles display a mononuclear inflammatory process, lumen occlusion by mucous plugging, goblet cell metaplasia, smooth muscle hyperplasia, and distortion due to fibrosis. These changes, combined with loss of supporting alveolar attachments, cause airflow limitation by allowing airway walls to deform and narrow the airway lumen.

Emphysema

Emphysema has 3 morphologic patterns. The first type, centriacinar emphysema, is characterized by focal destruction limited to the respiratory bronchioles and the central portions of acinus. This form of emphysema is associated with cigarette smoking and is most severe in the upper lobes. The second type, panacinar emphysema, involves the entire alveolus distal to the terminal bronchiole. The panacinar type is most severe in the lower lung zones and generally develops in patients with homozygous alpha1-antitrypsin (AAT) deficiency. The third type, distal acinar emphysema or paraseptal emphysema, is the least common form and involves distal airway structures, alveolar ducts, and sacs. This form of emphysema is localized to fibrous septa or to the pleura and leads to formation of bullae. The apical bullae may cause pneumothorax. Paraseptal emphysema is not associated with airflow obstruction.

Chronic obstructive pulmonary disease

Both emphysematous destruction and small airway inflammation often are found in combination in individual patients, leading to the spectrum that is known as COPD. When emphysema is moderate or severe, loss of elastic recoil, rather than bronchiolar disease, is the mechanism of airflow limitation. By contrast, when emphysema is mild, bronchiolar abnormalities are most responsible for the deficit in lung function. Although airflow obstruction in emphysema is often irreversible, bronchoconstriction due to inflammation accounts for a limited amount of reversibility.

Furthermore, airflow limitation is not the only pathophysiologic mechanism by which symptoms occur. Lung volumes, particularly dynamic hyperinflation, have also been shown to play a crucial role in the development of dyspnea perceived during exercise. In fact, the improvement in exercise capacity brought about by several treatment modalities, including bronchodilators, oxygen therapy, lung volume reduction surgery (LVRS), and pulmonary rehabilitation, are more likely due to delaying dynamic hyperinflation rather than improving the degree of airflow obstruction.^{5,6,7,8,9,10,11,12,13} Additionally, hyperinflation (as defined as the ratio of inspiratory capacity to total lung capacity [IC/TLC]) has been shown to predict survival better than forced expiratory volume in 1 second (FEV₁ ).¹⁴ 

Role of inflammation in COPD

In contrast to the eosinophil, which is the most prominent inflammatory cell in persons with asthma, the cellular composition of the airway inflammation in COPD is predominantly mediated by the neutrophils. Cigarette smoking induces macrophages to release neutrophil chemotactic factors and elastases, thus unleashing tissue destruction. Severity of airflow obstruction has correlated with greater induced sputum neutrophilia that is also more prevalent in patients with chronic cough and sputum production and is associated with an accelerated decline in lung function.

Macrophages also play an important role through macrophage-derived matrix metalloproteinases (MMPs). Cigarette smoke causes neutrophil influx and is required for the secretion of MMPs, therefore suggesting that both neutrophils and macrophages are required for the development of emphysema. Studies have also shown that T lymphocytes, particularly CD8⁺, in addition to the macrophages, play an important role in the pathogenesis of smoking-induced airflow limitation. To support the inflammation hypothesis further, a stepwise increase in alveolar inflammation occurs in surgical specimens from patients without COPD versus patients with mild or severe emphysema.

Indeed, mounting evidence supports that the dysregulation of apoptosis and defective clearance of apoptotic cells by macrophages play a prominent role in airway inflammation, particularly in emphysema.¹⁵ Azithromycin has been shown to improve this macrophage function, providing yet another possible modality of treatment in the future.¹⁶ 

Chronic obstructive pulmonary disease (COPD). Gross pathology of advanced emphysema. Large bullae are present on the surface of the lung.

Chronic obstructive pulmonary disease (COPD). Gross pathology of a patient with emphysema showing bullae on the surface.

Frequency

United States

The exact prevalence of COPD in the United States, as in the rest of the world, is unknown. This is largely due to the fact that it is an underdiagnosed (and undertreated) disease. The most recent study estimates a prevalence of 10.1% in the United States.¹⁷ 

International

The exact prevalence worldwide is largely unknown, but estimates have varied from 7-19%. The most recent study suggests a global prevalence of 10.1% (the same as in the United States alone).¹⁸ Men were found to have a prevalence of 11.8% and women 8.5%. The numbers vary in different regions of the world. Capetown, South Africa has the highest prevalence, affecting 22.2% of men and 16.7% of women. Hannover, Germany, on the other hand, has the lowest prevalence of 8.6% for men and 3.7% for women.

As noted above, whatever estimates are reported are widely believed to be underestimates because COPD is known to be an underdiagnosed and undertreated disease. Additionally, the prevalence in women is believed to be increasing.

Mortality/Morbidity

Absolute mortality rates for US patients aged 55-84 years (1985) were 200 deaths per 100,000 males and 80 deaths per 100,000 females. Internationally, a marked variation exists in overall mortality rates from COPD. The extremes are the more than 400 deaths per 100,000 males aged 65-74 years in Romania and the fewer than 100 deaths per 100,000 population in Japan.

COPD is the fourth leading cause of death in the United States.

Sex

Although currently the rates in men are higher than the rates in women, the rates in women have been increasing.

Clinical

History

Most patients with chronic obstructive pulmonary disease (COPD) have smoked at least 20 cigarettes per day for 20 or more years before the onset of the common symptoms of cough, sputum, and dyspnea. Presentation commonly occurs in the fifth decade of life.

• A productive cough or an acute chest illness is common. The cough usually is worse in the mornings and produces a small amount of colorless sputum.
• Breathlessness is the most significant symptom, but it usually does not occur until the sixth decade of life (although it may occur much earlier). By the time the FEV₁ has fallen to 30% of predicted, the patient is usually breathless after minimal exertion. In fact, the FEV₁ is the most common variable used to grade the severity of COPD, although it is not the best predictor of mortality (see Staging).
• Wheezing may occur in some patients, particularly during exertion and exacerbations.
• With disease progression, intervals between acute exacerbations become shorter, and each exacerbation may be more severe.
• COPD is now known to be a disease with systemic manifestations, and the quantification of these manifestations has proved to be a better predictor of mortality than lung function alone. Many patients with COPD may have decreased fat-free mass, impaired systemic muscle function, osteoporosis, anemia, depression, pulmonary hypertension, cor pulmonale, and even left-sided heart failure (see Staging).

Physical

The sensitivity of a physical evaluation for detecting mild-to-moderate chronic obstructive pulmonary disease (COPD) is relatively poor; however, the physical signs are quite specific and sensitive for severe disease. Patients with severe disease experience tachypnea and respiratory distress with simple activities.

• The respiratory rate increases proportionally to disease severity. Use of accessory respiratory muscles and paradoxical indrawing of lower intercostal spaces is evident (known as the Hoover sign). In advanced disease, cyanosis, elevated jugular venous pulse (JVP), and peripheral edema are observed.
• Measurement of forced expiratory time maneuver is a simple bedside test; a forced expiratory time of more than 6 seconds indicates considerable expiratory flow obstruction. Bedside spirometry is another test that can be used, which can actually help quantify the severity of obstruction by virtue of the FEV₁ .
• Thoracic examination reveals hyperinflation (barrel chest), wheezing, diffusely decreased breath sounds, hyperresonance on percussion, and prolonged expiration. Coarse crackles beginning with inspiration may be heard, and wheezes frequently are heard on forced and unforced expiration.

Causes

• Cigarette smoking
• The primary cause of chronic obstructive pulmonary disease (COPD) is exposure to tobacco smoke. Clinically significant COPD develops in 15% of cigarette smokers, although this number is believed to be an underestimate. Age of initiation of smoking, total pack-years, and current smoking status predict COPD mortality. People who smoke have a greater annual decline in FEV₁. Overall, tobacco smoking accounts for as much as 90% of the risk.
• Secondhand smoke, or environmental tobacco smoke, increases the risk of respiratory infections, augments asthma symptoms, and causes a measurable reduction in pulmonary function.
• Air pollution
• Although the role of air pollution in the etiology of COPD is unclear, the effect is small when compared with cigarette smoking.
• The use of solid fuels for cooking and heating may result in high levels of indoor air pollution and the development of COPD.
• Airway hyperresponsiveness
• Airway hyperresponsiveness (ie, Dutch hypothesis) stipulates that patients who have nonspecific airway hyperreactivity and who smoke are at increased risk of developing COPD with an accelerated decline in lung function. Nonspecific airway hyperreactivity is inversely related to FEV₁ and may predict a decline in lung function.
• The possible role of airway hyperresponsiveness as a risk factor for the development of COPD in people who smoke is unclear. Moreover, bronchial hyperreactivity may result from airway inflammation observed with the development of smoking-related chronic bronchitis. This may contribute to airway remodeling, leading to a more fixed obstruction as is seen in persons with COPD.
• Alpha1-antitrypsin deficiency
• AAT deficiency is the only known genetic risk factor for developing COPD and accounts for less than 1% of all cases in the United States. AAT is a protease inhibitor produced by the liver that acts predominantly by inhibiting neutrophil elastase in the lungs.
• Severe AAT deficiency leads to premature emphysema at the average age of 53 years for nonsmokers and 40 years for smokers.
• PiMM phenotypes occur in 90% of people and produce serum levels within the reference range. PiZZ is the most common deficient state and accounts for 95% of people in the severely deficient category.

Differential Diagnoses

Alpha1-Antitrypsin Deficiency	Pneumonia, Bacterial
Asthma	Pneumonia, Community-Acquired
Bronchiectasis	Pneumonia, Viral
Bronchitis	Pneumothorax
Chronic Bronchitis	Pulmonary Embolism
Cyanosis	Pulmonary Fibrosis, Idiopathic
Diaphragmatic Paralysis	Pulmonary Fibrosis, Interstitial (Nonidiopathic)
Emphysema	Respiratory Failure
Farmer's Lung	Restrictive Lung Disease
Hypersensitivity Pneumonitis	Tracheomalacia
Injecting Drug Use	Ventilation, Mechanical
Nicotine Addiction	Ventilation, Noninvasive
Perioperative Pulmonary Management

Other Problems to Be Considered

• Congestive heart failure is differentiated by the presence of fine basal crackles, by findings on chest radiographs, and by nonobstructed pulmonary function test (PFT) results.
• In bronchiectasis, patients produce a large amount of purulent sputum, coarse crackles are present, and clubbing occurs; abnormalities appear on chest radiographs.
• Bronchiolitis obliterans affects younger people with rheumatoid arthritis or with certain fume exposures (but is not associated with cigarette smoke); CT scans may show areas of mosaic perfusion.
• Chronic asthma is difficult to distinguish in older patients; the important distinction is a large bronchodilator response. Chronic airway inflammation as seen in asthma may lead to airway remodeling and a more fixed obstruction as seen in COPD.

Workup

Laboratory Studies

Secondary polycythemia due to chronic hypoxemia may develop in persons with severe chronic obstructive pulmonary disease (COPD) or in those patients who smoke excessively. A hematocrit value of more than 52% in males and more than 47% in female indicates disease.

Measure the alpha1-antitrypsin (AAT) levels in all patients younger than 40 years or in those with a family history of emphysema at an early age. If the AAT level is low, then phenotyping should be performed.

• Sputum
• In persons with stable chronic bronchitis, sputum is mucoid and macrophages are the predominant cell. With an exacerbation, sputum becomes purulent because of the presence of neutrophils. A mixture of organisms often is visible after a Gram stain.
• The pathogens most frequently cultured during exacerbations are Streptococcus pneumoniae andHaemophilus influenzae. Moraxella catarrhalis is also a common organism, and Pseudomonas aeruginosa can be seen in patients with severe obstruction.

Imaging Studies

• Chest radiography
• Frontal and lateral chest radiographs reveal signs of hyperinflation, including a flattening of the diaphragm, increased retrosternal air space, and a long narrow heart shadow. Rapid-tapering vascular shadows accompanied by hyperlucency of the lungs are signs of emphysema.
• With complicating pulmonary hypertension, the hilar vascular shadows are prominent, with possible right ventricular enlargement and opacity in the lower retrosternal air space.

Posteroanterior (PA) and lateral chest radiograph in a patient with severe chronic obstructive pulmonary disease (COPD). Hyperinflation, depressed diaphragms, increased retrosternal space, and hypovascularity of lung parenchyma is demonstrated.

Chronic obstructive pulmonary disease (COPD). A lung with emphysema shows increased anteroposterior (AP) diameter, increased retrosternal airspace, and flattened diaphragms on lateral chest radiograph.

Chronic obstructive pulmonary disease (COPD). A lung with emphysema shows increased anteroposterior (AP) diameter, increased retrosternal airspace, and flattened diaphragms on posteroanterior chest radiograph.

• Computed tomography scanning
• High-resolution CT (HRCT) scanning is more sensitive than standard chest radiography.
• HRCT scanning is highly specific for diagnosing emphysema, and the outlined bullae are not always visible on a radiograph. HRCT scanning may provide an adjunct to diagnosing various forms of COPD (ie, lower lobe disease may suggest AAT deficiency) and may help determine if surgical intervention would be of benefit to the patient.

Chronic obstructive pulmonary disease (COPD). A CT scan shows hyperlucency due to hypovascularity and bullae formation diffusely, predominantly in upper lobes.

Severe bullous disease observed on CT scan in a patient with chronic obstructive pulmonary disease (COPD).

• Two-dimensional echocardiography

• Many patients with long-standing COPD develop secondary pulmonary hypertension from chronic hypoxemia and vascular remodeling. This may result in eventual right-sided heart failure (cor pulmonale).
• Two-dimensional echocardiography may be helpful as a screening tool to estimate pulmonary arterial systolic pressure and right ventricular systolic function.

Other Tests

• Pulmonary function tests
• These measurements are essential for the diagnosis and assessment of the severity of disease, and they are helpful in following its progress.
• Forced expiratory volume in 1 second (FEV₁) is a reproducible test and is the most commonly used index of airflow obstruction.
• Lung volume measurements  often show an increase in total lung capacity, functional residual capacity, and residual volume. The vital capacity often decreases. Dynamic hyperinflation during exercise is now thought be a greater contributor to the sensation of dyspnea than airflow obstruction alone (as measured by FEV₁).
• Carbon monoxide diffusing capacity is decreased in proportion to the severity of emphysema.
• Arterial blood gas analysis reveals mild-to-moderate hypoxemia without hypercapnia in the early stages. As the disease progresses, hypoxemia becomes more severe and hypercapnia supervenes. Hypercapnia commonly is observed as the FEV₁ falls below 1 L/s or 30% of the predicted value. The lung mechanics and gas exchange worsen during acute exacerbations.
• As many as 30% of patients have an increase in FEV₁ by 15% or more after inhalation of a bronchodilator. However, the absence of bronchodilator response does not justify withholding therapy.

Chronic obstructive pulmonary disease (COPD). Pressure volume curve comparing lungs with emphysema lungs and restrictive lungs to normal lungs.

Chronic obstructive pulmonary disease (COPD). Flow volume curve of lungs in emphysema shows marked decrease in expiratory flows, hyperinflation, and air trapping (patient B) compared to a patient with restrictive lung disease, who has reduced lung volumes and preserved flows (patient A).

Chronic obstructive pulmonary disease (COPD). Forced expiratory volume in 1 second (FEV1) can be used to evaluate the prognosis in patients with emphysema. The benefit of smoking cessation is shown here because the deterioration in lung function parallels that of a nonsmoker, even in late stages of the disease. Redrawn from Fletcher C, Peato R. The natural history of chronic airflow obstruction. Br Med J 1977; 1: 1645-1648.

  

• Six-minute walking distance
• The distance walked in 6 minutes is a good predictor of all-cause and respiratory mortality in patients with moderate COPD.^13,19
• Patients with COPD who desaturate during the 6-minute walking distance (6MWD) have a higher mortality rate than those who do not desaturate.
• Consequently, this test is used as a part of the multidimensional BODE index (body mass index, obstruction [FEV₁], dyspnea [ie, Medical Research Council Dyspnea Scale], and exercise capacity [ie, 6MWD]) designed to help predict mortality in COPD patients (see Staging).

Procedures

• Right-sided heart catheterization: If pulmonary hypertension is suggested based on the clinical examination findings or on estimates from a 2-dimensional echocardiogram, then a right-sided heart catheterization may be preformed to directly measure the pulmonary artery pressures and their responsiveness to vasodilators.

Histologic Findings

Chronic obstructive pulmonary disease (COPD). Histopathology of chronic bronchitis showing hyperplasia of mucous glands and infiltration of the airway wall with inflammatory cells.

Chronic obstructive pulmonary disease (COPD). Histopathology of chronic bronchitis showing hyperplasia of mucous glands and infiltration of the airway wall with inflammatory cells (high-powered view).

Chronic obstructive pulmonary disease (COPD). At high magnification, in emphysema, loss of alveolar walls and dilatation of airspaces occurs.

Staging

Until recently, the severity of airflow obstruction has been the mainstay of staging chronic obstructive pulmonary disease (COPD). The American Thoracic Society (ATS) has provided criteria for staging COPD based on the presence of obstruction (ratio of FEV₁ to forced vital capacity [FEV₁/FVC] <70%) and its severity as measured by percent of predicted FEV₁. The GOLD guidelines have taken staging one step further by incorporating the presence or absence of signs/symptoms in its most severe stage. Furthermore, they have provided guidelines for therapy based on the Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage. These staging systems, however, have limited utility in trying to predict mortality.

For a guideline summary, see Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonarydisease.² 

The recognition that COPD is a systemic disease has helped develop criteria that are better at predicting mortality than airway obstruction alone. The most widely used staging system in this regard is the BODE index. The multidimensional nature of this index helps physicians determine a more comprehensive assessment of the severity of disease.

• ATS criteria for assessing the severity of airflow obstruction (based on the percent predicted postbronchodilator FEV₁ when the FEV₁/FVC is <70%)
• Stage I (mild) - FEV₁ greater than or equal to 80% of predicted.
• Stage II (moderate) - FEV₁ less than 80% and greater than or equal to 50% of predicted
• Stage III (severe) - FEV₁ less than 50% and greater than or equal to 30% of predicted
• Stage IV (very severe) - FEV₁ less than 30% of predicted or FEV₁ less than 50% and chronic respiratory failure
• GOLD guidelines

• Stage I (mild obstruction) - Reduction of risk factors (influenza vaccine) plus short-acting bronchodilator as needed
• Stage II (moderate obstruction) - Reduction of risk factors (influenza vaccine) plus short-acting bronchodilator as needed plus long-acting bronchodilator(s) plus cardiopulmonary rehabilitation
• Stage III (severe obstruction) - Reduction of risk factors (influenza vaccine) plus short-acting bronchodilator as needed plus long-acting bronchodilator(s) plus cardiopulmonary rehabilitation plus inhaled glucocorticoids if repeated exacerbations
• Stage IV (very severe obstruction or moderate obstruction with evidence of chronic respiratory failure) - Reduction of risk factors (influenza vaccine) plus short-acting bronchodilator as needed plus long-acting bronchodilator(s) plus cardiopulmonary rehabilitation plus inhaled glucocorticoids if repeated exacerbations plus long-term oxygen therapy (if criteria met); also consider surgical options
• BODE index
• Body mass index
• Greater than 21 = 0 points
• Less than 21 = 1 point
• FEV₁ (postbronchodilator percent predicted)
• Greater than 65% = 0 points
• 50-64% = 1 point
• 36-49% = 2 points
• Less than 35% = 3 points
• MMRC dyspnea scale
• MMRC 0 = Dyspneic on strenuous exercise (0 points)
• MMRC 1 = Dyspneic on walking a slight hill (0 points)
• MMRC 2 = Dyspneic on walking level ground; must stop occasionally due to breathlessness (1 point)
• MMRC 3 = Dyspneic after walking 100 yards or a few minutes (2 points)
• MMRC 4 = Cannot leave house; dyspneic doing activities of daily living (3 points)
• Six-minute walking distance
• Greater than 350 meters = 0 points
• 250-349 meters = 1 point
• 150-249 meters = 2 points
• Less than 149 meters = 3 points
• Approximate 4-year survival
• 0-2 points = 80%
• 3-4 points = 67%
• 5-6 points = 57%
• 7-10 points = 18%

Treatment

Medical Care

The goal of chronic obstructive pulmonary disease (COPD) management is to improve daily living and the quality of life by preventing symptoms and the recurrence of exacerbations by preserving optimal lung function. Once the diagnosis of COPD is established, it is important to educate the patient about the disease and encourage them to actively participate in therapy.
Smoking cessation continues to be the most important therapeutic intervention. Most patients with COPD have a history of smoking or are currently smoking tobacco products. A smoking cessation plan is an essential part of a comprehensive management plan. The success rates are low because of the addictive power of nicotine, the conditioned response to smoking-associated stimuli, and psychological problems, including depression, poor education, and forceful promotional campaigns by the tobacco industry. The process of smoking cessation must involve multiple interventions.

Oral and inhaled medications are used for patients with stable disease to reduce dyspnea and improve exercise tolerance. Most of the medications used are directed at 4 potentially reversible causes of airflow limitation in a disease state that has largely fixed obstruction. The following factors may be present: (1) bronchial smooth muscle contraction, (2) bronchial mucosal congestion and edema, (3) airway inflammation, and (4) increased airway secretions.

Smoking cessation, physical intervention

The transition from smoking to not smoking occurs in 5 stages: precontemplation, contemplation, preparation, action, and maintenance. Smoking intervention programs include self-help, group, physician-delivered, workplace, and community programs.

Setting a quit date may be helpful. Physicians and other healthcare providers should participate in setting the target date and follow-up with respect to maintenance.

Successful cessation programs usually use the following resources and tools: patient education, a quit date, follow-up support, relapse prevention, advice for healthy lifestyle changes, social support systems, and adjuncts to treatment (eg, pharmacological agents). Mottillo et al reported meta-analysis results that conclude intensive behavioral intervention, including individual counseling and telephone counseling, among other, offers considerable benefit for increasing smoking abstinence.²⁰ 

According to the US Preventive Services Task Force (USPSTF) guidelines, clinicians should ask all adults about use of tobacco products and provide cessation interventions to current users. The guideline engages a "5-A" approach to counseling that includes the following²¹ :

• Ask about tobacco use.
• Advise to quit through personalized messages.
• Assess willingness to quit.
• Assist with quitting.
• Arrange follow-up care and support.

Brief behavioral counseling (ie, <10 min) and pharmacotherapy are each effective alone—although they are most effective when used together. The task force also advises clinicians to ask all pregnant women, regardless of age, about tobacco use. Those who currently smoke should receive pregnancy-tailored counseling supplemented with self-help materials.

Smoking cessation, pharmacologic intervention

Supervised use of pharmacologic agents is an important adjunct to self-help and group smoking cessation programs.

Nicotine is the ingredient in cigarettes primarily responsible for the addiction. Withdrawal from nicotine may cause unpleasant adverse effects, including anxiety, irritability, difficulty concentrating, anger, fatigue, drowsiness, depression, and sleep disruption. These effects usually occur during the first several weeks.

Nicotine replacement therapies after smoking cessation reduce withdrawal symptoms. If a smoker requires his or her first cigarette within 30 minutes of waking up, they most likely are highly addicted and would benefit from nicotine replacement therapy.

Several nicotine replacement therapies are available. Nicotine polacrilex is a chewing gum and has better quit rates than counseling alone. Nicotine replacement therapy chewing pieces are marketed in 2 strengths (ie, 2 mg, 4 mg). An individual who smokes 1 pack per day should use 4-mg pieces. The 2-mg pieces are to be used by individuals who smoke less than 1 pack per day. Instruct the patient to chew hourly and also to chew when needed for their initial cravings for 2 weeks. Gradually reduce the amount chewed over the next 3 months.

Transdermal nicotine patches are available readily for replacement therapy. Long-term success rates are 22-42%, compared with 2-25% with a placebo. These agents are well tolerated, and the adverse effects are limited to localized skin reaction. Nicotine replacement therapy patches are sold under the following trade names: NicoDerm, Nicotrol, and Habitrol. Each of these products is dosed with a scheduled graduated decrease in nicotine over 6-10 weeks.

The use of the antidepressant bupropion (Zyban) is also effective for smoking cessation. This nonnicotine aid to smoking cessation enhances central nervous nonadrenergic function. One study demonstrated that 23% of patients sustained cessation at 1 year, compared with 12% who sustained cessation with the placebo. Bupropion may also be effective in patients who not been able to quit smoking with nicotine replacement therapy.

The most recent drug to receive approval for smoking cessation is varenicline (Chantix). Varenicline is a partial agonist selective for alpha4, beta2 nicotinic acetylcholine receptors. Action is thought to result from activity at a nicotinic receptor subtype, where its binding produces agonist activity while simultaneously preventing nicotine binding. Agonistic activity is significantly lower than nicotine.

Bronchodilators

The use of bronchodilators is guided by some very important concepts. In some patients, the change in forced expiratory volume in 1 second (FEV₁) may be small; however, benefit may be seen by some other mechanism, such as decreased hyperinflation (hence, lack of a bronchodilator response on pulmonary function testing should not preclude their use if clinically warranted). Furthermore, some patients may have difficulty achieving effective delivery of the medication using a metered-dose inhaler; hence, use of a spacer may be of benefit to the patient. Finally, inhaled delivery of medications is preferred over the oral route to help minimize potential adverse effects. Further, generally speaking, long-acting bronchodilators are more beneficial than short-acting ones.^6,12,22 

Beta-agonists 

Inhaled beta2-agonist bronchodilators activate specific B2-adrenergic receptors on the surface of smooth muscle cells, which increases intracellular cyclic adenosine monophosphate (AMP) and smooth muscle relaxation. Patients, even those who have no measurable increase in expiratory flow, may benefit from treatment using beta2 agonists.

In COPD, beta2 agonists produce less bronchodilatation compared with asthma. Patients primarily use beta2 agonists for relief of symptoms of COPD. In patients with mild intermittent symptoms, it is recommended to use a short-acting beta2 agonist for symptomatic relief. In patients with more persistent symptoms, a long-acting beta agonist should be used. Long-acting beta agonists have been shown to increase exercise endurance, prevent nocturnal dyspnea, and improve quality of life. See Staging for specific treatment recommendations.

Anticholinergic agents 

Anticholinergic drugs compete with acetylcholine for postganglionic muscarinic receptors, thereby inhibiting cholinergically mediated bronchomotor tone, resulting in bronchodilatation. They block vagally mediated reflex arcs that cause bronchoconstriction. The clinical benefit is gained through a decrease in exercise-induced dynamic hyperinflation.

Short-acting anticholinergics such as ipratropium bromide in patients with stable COPD have been shown to have equivalent or superior activity when compared with a beta2 agonist. However, in combination with a beta2 agonist, synergistic effect on bronchodilatation occurs. This medication has slower onset and a longer duration than a beta2 agonist and is less suitable for use on an as-needed basis.

Typically, ipratropium bromide is administered 2-4 puffs every 6-8 hours. Tiotropium is a once-daily, long-acting anticholinergic medication that has been shown to have significant clinical benefit and is a first-line therapy in patients with persistent symptoms (see Staging). Although the results of the Understanding Potential Long Term Impacts on Function With Tiotropium trial (UPLIFT) did not show a change in the rate of decline of FEV₁ or mortality when compared with placebo, it did show a significant reduction in frequency of COPD exacerbations and hospitalizations and an improvement in quality of life.^23,24,25,26 

Phosphodiesterase inhibitors 

Methylxanthines (ie, theophylline) are nonspecific phosphodiesterase inhibitors that increase cyclic AMP within the airway smooth muscle of the airways. Additionally, they may improve diaphragm muscle contractility and stimulate the respiratory center.

Adding theophylline to the combination of bronchodilators can result in further benefit in stable COPD patients. However, the narrow therapeutic index of theophylline has caused a decline in its popularity. Patients metabolize theophylline primarily by the hepatic enzyme system, a process affected by age, the heart, and liver abnormalities. Serum levels of theophylline need to be monitored because of the potential for toxicity. Adverse effects include anxiety, tremors, insomnia, nausea, cardiac arrhythmia (particularly multifocal atrial tachycardia), and seizures. Hence, the previously recommended target range of 15-20 mg/dL has now been reduced to 8-13 mg/dL.

Second-generation specific phosphodiesterase IV inhibitors include cilomilast and roflumilast. They cause a reduction of the inflammatory process (macrophages and CD8⁺ lymphocytes) in patients with COPD. Cilomilast is completely absorbed following oral administration and its elimination half-life is approximately 6.5 hours. A dose of 15 mg twice daily has been found to be clinically effective. Nausea, presumably of central origin, is the principal adverse reaction. Preliminary clinical studies suggest a favorable clinical effect in COPD; however, these need to be confirmed in larger trials.

Roflumilast, a phosphodiesterase-4 inhibitor currently under investigation for use in the United States, exhibits anti-inflammatory effects, including reduced airway inflammation and improved lung function in patients with COPD. To analyze the impact of roflumilast on the incidence of COPD exacerbations requiring corticosteroids, Calverley et al performed 2 randomized, double-blind, placebo-controlled multicenter trials. Patients with COPD were randomly assigned to receive roflumilast or placebo for 52 weeks. Both studies revealed increased FEV₁ in patients who received roflumilast compared with placebo (P <.0001). In addition, the rate of COPD exacerbations was reduced by 17% in patients who received roflumilast compared with placebo (P <.0003).²⁷ 

Anti-inflammatory medications

Steroids 

Corticosteroids are potent anti-inflammatory medications that affect the inflammatory cascade at multiple points. In the oral form, their primary role is for the treatment of exacerbations. The goal, however, is to wean from the steroid as soon as the patient can clinically tolerate it because of the concern for potential well-known systemic adverse effects. However, a small portion of patients may require long-term corticosteroid use to keep their symptoms under control. Note that oral steroids are not as effective in treating COPD exacerbations as they are for bronchial asthma exacerbations.

Inhaled corticosteroids provide a more direct route of administration to the airways. Consequently, aside from the development of thrush, the systemic adverse effects of these medications at standard doses are negligible. Although inhaled corticosteroids have not been shown to significantly reduce the rate of loss of lung function, in past studies they have been shown to reduce the frequency of exacerbations and slow the rate of loss of health-related quality of life. The Towards a Revolution in COPD Health (TORCH) trial, however, showed that a combination of an inhaled corticosteroid and a long-acting beta-agonist was more beneficial than inhaled corticosteroids alone.²⁸ Additionally, those treated with inhaled corticosteroids were noted to have an increased rate of pneumonia. These data suggest that in patients with COPD, inhaled corticosteroids should only be used in conjunction with a long-acting beta-agonist.

Debate continues regarding use of inhaled corticosteroids and the risk for pneumonia in patients with COPD. Sin et al analyzed data from 7 large clinical trials (n = 7042) of patients with stable COPD who used inhaled budesonide (n = 3801) or a control regimen (placebo or formoterol alone). No significant difference was recorded for pneumonia occurrence between the budesonide group (3%; n = 122) and the control group (3%; n = 103). Increasing age and decreasing percent of predicted FEV₁ were the only variables that were significantly associated with pneumonia occurrence.²⁹ 

Nonsteroidal anti-inflammatory medications 

Nonsteroidal anti-inflammatory medications have not been conclusively shown to have any benefit in COPD. Medications targeting interleukin 8 and tumor necrosis factor-alpha did not show any response. Leukotriene inhibitors commonly used in asthma have also not proven to be beneficial in COPD.

Macrolide antibiotics, however, have been shown to have anti-inflammatory effects in the airways of COPD patients. More specifically, azithromycin has been shown to improve phagocytic function of pulmonary macrophages and be a potent anti-inflammatory.¹⁶ Azithromycin is clinically used for its anti-inflammatory effects in patients with cystic fibrosis and in lung transplantation patients with chronic rejection. Furthermore, one study showed that erythromycin reduced the frequency of exacerbations in 109 patients with COPD treated over 12 months.³⁰ These results, however, need to be validated in a larger study before such therapy can be recommended.

Antibiotics

In patients with COPD, chronic infection or colonization of the lower airways is common from Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis. In patients with chronic severe airways obstruction, Pseudomonas aeruginosa infection also may be prevalent.
Empiric antimicrobial therapy is recommended in patients with an acute exacerbation (as evidenced by an increase in baseline dyspnea and/or a change in the quantity or quality of cough) and evidence of an infectious process, such as fever, leukocytosis, or an infiltrate on chest radiograph. The antibiotic choice must be comprehensive and should cover all likely pathogens in the context of the clinical setting and local resistance patterns.¹ 

Mucolytic agents

These agents reduce sputum viscosity and improve secretion clearance. Viscous lung secretions in patients with COPD consist of mucous-derived glycoproteins and leukocyte-derived DNA.

The oral agent N -acetylcysteine has antioxidant and mucokinetic properties and is used to treat patients with COPD. However, the efficacy of mucolytic agents in the treatment of COPD remains controversial, as they have also been shown to elicit bronchospasm.

Proton pump inhibitors 

Sasaki et al conducted a randomized, observer-blind, controlled trial to determine if proton pump inhibitors (PPIs) reduce the incidence of common colds in patients with COPD. Patients (n = 100) were assigned to conventional therapy (control group) or conventional therapy plus PPI (lansoprazole 15 mg/d). The frequency of common colds and COPD exacerbations was measured, and the number of exacerbations per person over 12 months was significantly lower in the PPI group compared with the control group (P <.001). No significant difference in the numbers of common colds was observed between the PPI group and the control group. The authors concluded that although lansoprazole showed a significant decrease in COPD exacerbations, more definitive clinical trials are required.³¹ 

Oxygen therapy

COPD commonly is associated with progressive hypoxemia. Oxygen administration reduces mortality rates in patients with advanced COPD because of the favorable effects on pulmonary hemodynamics.

Two landmark trials, the British Medical Research Counsel (MRC study) and the National Heart, Lung, Blood Institutes Nocturnal Oxygen Therapy Trial (NOTT), showed that long-term oxygen therapy improves survival 2-fold or more in hypoxemic patients with COPD. Hypoxemia is defined as PaO₂ of less than 55 mm Hg or oxygen saturation of less than 90%. Oxygen was used from 15-19 h/d.

Specialists recommend long-term oxygen therapy, therefore, for patients with a PaO₂ of less than 55 mm Hg, a PaO₂ of less than 59 mm Hg with evidence of polycythemia, or cor pulmonale. Reevaluate these patients 1-3 months after initiating therapy because some patients may not require long-term oxygen.

Many patients with COPD who are not hypoxemic at rest worsen during exertion. Home supplemental oxygen commonly is prescribed for these patients. Oxygen supplementation during exercise can prevent increases in pulmonary artery pressure, reduce dyspnea, and improve exercise tolerance. However, a study from 2008 demonstrated that patients with COPD-related hypoxemia and exertional desaturation who completed a program of pulmonary rehabilitation failed to show any benefit in domestic activity, health-related quality of life, or time spent outside of home in those treated with oxygen compared with placebo.³² Hence, the benefits of home ambulatory oxygen for this subset of patients remain controversial.

Oxygen therapy generally is safe. Oxygen toxicity from high-inspired concentrations (ie, >60%) is well recognized. Little is known about the long-term effects of low-flow oxygen. The increased survival and quality-of-life benefits of long-term oxygen therapy outweigh the possible risks. PaCO₂ retention from depression of hypoxic drive has been overemphasized. PaCO₂ retention is more likely a consequence of ventilation/perfusion mismatching rather than respiratory center depression. While this complication is not common, it is best avoided by titration of oxygen delivery to maintain PaO₂ at 60-65 mm Hg.

The major physical hazards of oxygen therapy are fires or explosions. Patients, family, and other caregivers must be warned not to smoke. Overall, major accidents are rare and can be avoided by good patient and family training.

Oxygen delivery systems

The continuous flow nasal cannula is the standard means of oxygen delivery for the stable hypoxemic patient. It is simple, reliable, and generally well tolerated. Each liter of oxygen flow adds 3-4% to the fraction of inspired oxygen (FiO₂). Nasal oxygen delivery also is beneficial for most mouth-breathing patients. Humidification generally is not beneficial when the patient receives oxygen by nasal cannula at flows of less than 5 L/min.

Oxygen conserving devices function by delivering all of the supplemental oxygen during early inhalation. These devices improve the portability of oxygen therapy and may reduce overall costs. Three distinct oxygen-conserving devices exist—reservoir cannulas, demand pulse delivery devices, and transtracheal oxygen delivery.

Transtracheal oxygen delivery involves the insertion of a catheter percutaneously between the second and third tracheal interspace. Transtracheal oxygen delivery is invasive and requires special training by the physician, the patient, and the caregiver. The procedure has risks as well as medical benefits but has limited application.

Noninvasive positive-pressure ventilation

Noninvasive positive-pressure ventilation (NIPPV), as the name suggests, allows the delivery of positive-pressure ventilation without the use of an endotracheal tube. In place of the tube is a tight-fitting nasal or facial mask, which is then attached to a continuous positive airway pressure (CPAP) or a bilevel positive airway pressure (BiPAP) machine. The positive pressure is beneficial in hypercapneic respiratory failure by decreasing the work of breathing, allowing a larger tidal volume for a given respiratory effort, hence improving alveolar ventilation.

NIPPV has been shown to have significant benefit in select patients with acute hypercapneic respiratory failure due to COPD, including a reduction in the need for endotracheal intubation, reduced hospital stay, and a mortality benefit.^33,34 This modality should not be used in patients who are unable to protect their airway, are hemodynamically unstable, have significant secretions, are uncooperative, or have an Acute Physiology and Chronic Health Evaluation (APACHE) score of greater than 29.³⁵ 

One study also suggests that in patients with chronic hypercapneic respiratory failure who are undergoing pulmonary rehabilitation, nocturnal NIPPV may improve quality of life, daytime PaCO₂, and exercise tolerance.³⁶ 

Chronic obstructive pulmonary disease (COPD). Pulmonary rehabilitation.

Chronic obstructive pulmonary disease (COPD). Pulmonary rehabilitation.

Chronic obstructive pulmonary disease (COPD).

Chronic obstructive pulmonary disease (COPD). Bilevel positive airway pressure (BiPAP).

Surgical Care

Over the past 50-75 years, researchers have described a variety of surgical approaches to improve symptoms and restore function in patients who have emphysema. The following are the most commonly used:

• Bullectomy
• Removal of giant bullae has been a standard approach in selected patients for many years.
• The bullae in patients with emphysema generally range from 1-4 cm in diameter; however, on occasion, bullae can occupy more than 33% of the hemithorax (eg, giant bullae).
• Giant bullae may compress adjacent lung tissue, thereby reducing the blood flow and ventilation to the healthy tissue. Removal of these bullae may result in the expansion of compressed lungs and improved function.
• Patients who are symptomatic and have an FEV₁ of less than 50% of the predicted value have a better outcome after bullectomy. This surgery is performed through midline sternotomy, a lateral incision, or by video-assisted thoracoscopy. Postoperative bronchopleural air leak is the major potential complication.
• Giant bullectomy can produce subjective and objective improvement in selected patients—in those who have bullae that occupy at least 30%, and preferably 50%, of the hemithorax and compress adjacent lung, who have FEV₁ of less than 50% of the predicted value, and who otherwise have relatively preserved lung function.
• Lung volume reduction surgery
• Nearly 40 years ago, Brantigan et al first reported resectional surgery for diffuse emphysema in 33 patients. They resected 20-30% of each lung that appeared most diseased. Brantigan hypothesized that removal of a portion of the emphysematous lung increased the radial traction on the airways in the remaining lung, improving expiratory airflow and mechanical function of the respiratory system, thereby reducing symptoms.
• The surgical approach uses a midline sternotomy with stapling of the lung margins. Surgeons generally resect 20-30% of each lung from the upper zones. The lung volume reduction surgery procedure has a mortality rate of 0-18%. Several complications, including pneumonia and prolonged air leaks, have been observed.
• Several studies, including the large multicenter National Emphysema Treatment Trial (NETT), have demonstrated significant benefit in spirometry, exercise tolerance, dyspnea, health-related quality of life, and mortality in select patients.³⁷ Those who benefit most are patients with heterogeneous (upper lobe) disease and a low exercise capacity despite optimal medical therapy and cardiopulmonary rehabilitation. Patients with an FEV₁ of less than 20% predicted and either homogenous disease or diffusing capacity of the lung for carbon dioxide (DLCO) of less than 20% predicted are considered high risk for this procedure.

• Lung transplantation
• Lung transplantation is a relatively new therapy for advanced lung disease. Lung transplantation is performed only at select tertiary care centers around the world. Patients with COPD are the largest single category of patients who undergo the procedure.
• When evaluating a potential candidate, several factors need be taken into account, including symptomatology, comorbid conditions, and projected survival without transplantation (the BODE index is commonly used for this purpose). Generally speaking, most centers set an age limit of 65 years.
• The mean survival after lung transplantation is 5 years. The survival at 1 year is 80-90%.^38,39Whether or not this procedure has any effect on the survival of COPD patients is controversial; however, the main purpose is to improve symptomatology and quality of life.

Diet

Inadequate nutritional status associated with low body weight in patients with COPD is associated with impaired pulmonary status, reduced diaphragmatic mass, lower exercise capacity, and higher mortality rates. Nutritional support is an important part of their comprehensive care.

Medication

The goals of pharmacotherapy are to reduce morbidity and to prevent complications. Additionally, the Medscape COPD Resource Center may be helpful.

Bronchodilators

These agents act to decrease muscle tone in both small and large airways in the lungs, thereby increasing ventilation. Category includes subcutaneous medications, beta-adrenergics, methylxanthines, and anticholinergics.

Tiotropium (Spiriva), a bronchodilator similar to ipratropium, is approved by the US Food and Drug Administration. Tiotropium is a quaternary ammonium compound. It elicits anticholinergic/antimuscarinic effects with inhibitory effects on M₃ receptors on airway smooth muscles, leading to bronchodilation. Tiotropium is available as a capsule dosage form containing a dry powder for oral inhalation via the HandiHaler inhalation device. For adults, the contents of one capsule (18 mcg) are inhaled every day via the HandiHaler device. Contraindications, drug interactions, and adverse effects are similar to those of ipratropium.

Albuterol (Proventil, Ventolin)

Beta-agonist for bronchospasm refractory to epinephrine. Relaxes bronchial smooth muscle by action on beta2-receptors with little effect on cardiac muscle contractility. Most patients (even those who have no measurable increase in expiratory flow) benefit from treatment. Inhaled beta agonists are prescribed initially as needed. May increase frequency. Institute regular schedule in patients on anticholinergic drugs who remain symptomatic. Available as liquid for nebulizer, metered-dose inhalers, and dry-powder inhalers.

·                                 Dosing

·                                 Interactions

·                                 Contraindications

·                                 Precautions

Adult

MDI: 2 puffs q3-4h
Nebulizer: 0.2-0.3 mL of 5% albuterol solution diluted to 2.5 mL with NS tid/qid; unit dose vials are available

Pediatric

MDI:
<12 years: Not recommended
>12 years: Administer as in adults
Nebulizer:
Infants and children: 0.01-0.02 mL of 5% solution diluted in 2-3 mL NS q4-6h
Adolescents: Administer as in adults

Metaproterenol (Alupent)

Relaxes bronchial smooth muscle by action on beta2-receptors with little effect on cardiac muscle contractility. Most patients (even those who have no measurable increase in expiratory flow) benefit from treatment. Inhaled beta agonists initially are prescribed as needed. Frequency may be increased. Institute regular schedule in patients on anticholinergic drugs who are still symptomatic. Available as liquid for nebulizer, metered-dose inhalers, and dry-powder inhalers.

·                                 Dosing

·                                 Interactions

·                                 Contraindications

·                                 Precautions

Adult

MDI: 2 puffs q3-4h
Nebulizer: 0.2-0.3 mL of 5% solution diluted to 2.5 mL with NS tid/qid

Pediatric

MDI:
<12 years: Not recommended
>12 years: Administer as in adults
Nebulizer:
Infants and children: 0.01-0.02 mL of 5% solution diluted in 2-3 mL NS q4-6h
Adolescents: Administer as in adults

Ipratropium (Atrovent)

Chemically related to atropine. Has antisecretory properties and, when applied locally, inhibits secretions from serous and seromucous glands lining the nasal mucosa. Used on a fixed schedule with beta agonist.

·                                 Dosing

·                                 Interactions

·                                 Contraindications

·                                 Precautions

Adult

MDI: 2-4 puffs q4-6h
Nebulizer: 250 mcg diluted with 2.5 mL NS q4-6h

Pediatric

MDI: 1-2 puffs tid; not to exceed 6 puffs per d
Nebulizer: 250 mcg tid

Theophylline (Aminophylline, Theo-24, Theo-Dur, Slo-bid)

Potentiates exogenous catecholamines. Stimulates endogenous catecholamine release and diaphragmatic muscular relaxation, which stimulates bronchodilation.
Popularity has decreased because of narrow therapeutic range and frequent toxicity. Bronchodilation may require near toxic (>20 mg/dL) levels. However, clinical efficacy is controversial, especially in the acute setting.
Shown to increase exercise capacity, decrease dyspnea, and improve gas exchange. A longer-acting agent is used qd or bid.
Target concentration is 10 mcg/mL. Dosing = (target concentration - current level) X 0.5 (ideal body weight). Alternatively, 1 mg/kg results in approximately 2-mcg/mL increase in serum levels.

·                                 Dosing

·                                 Interactions

·                                 Contraindications

·                                 Precautions

Adult

Initial: 10 mg/kg/d PO divided q8-12h
Maintenance: 10 mg/kg/d PO divided qd or bid; adjust dose in 25% increments to maintain serum theophylline level of 5-15 mcg/mL; not to exceed 800 mg/d

Pediatric

Children: 10 mg/kg/d PO divided doses q8-12h initial; 10 mg/kg/d PO qd or bid maintenance; adjust dose in 25% increments to maintain serum theophylline level of 5-15 mcg/mL; not to exceed 16 mg/kg/d

Salmeterol (Serevent)

By relaxing the smooth muscles of the bronchioles in conditions associated with bronchitis, emphysema, asthma, or bronchiectasis, salmeterol can relieve bronchospasms. Effect also may facilitate expectoration.
Shown to improve symptoms and morning peak flows. May be useful when bronchodilators are used frequently. More studies are needed to establish the role for these agents.
When administered at high or more frequent doses than recommended, incidence of adverse effects is higher. Bronchodilating effect lasts >12h. Used on a fixed schedule in addition to regular use of anticholinergic agents.

·                                 Dosing

·                                 Interactions

·                                 Contraindications

·                                 Precautions

Adult

2 puffs bid

Pediatric

<4 years: Not established
4-12 years: 1 inhalation (50 mcg) bid at least 12h apart
>12 years: Administer as in adults

Formoterol (Oxis, Foradil)

By relaxing the smooth muscles of the bronchioles in conditions associated with bronchitis, emphysema, asthma, or bronchiectasis, formoterol can relieve bronchospasms. Effect also may facilitate expectoration.
Shown to improve symptoms and morning peak flows. May be useful when bronchodilators are used frequently. More studies are needed to establish the role for these agents.
When administered at high or more frequent doses than recommended, incidence of adverse effects is higher. Bronchodilating effect lasts >12h. Used on a fixed schedule in addition to regular use of anticholinergic agents.

·                                 Dosing

·                                 Interactions

·                                 Contraindications

·                                 Precautions

Adult

12-25 mcg bid

Pediatric

Not established

Corticosteroids

A meta-analysis of 16 controlled trials in stable COPD found that approximately 10% of patients respond to these drugs. The responders should be identified carefully. An increase in FEV₁ >20% is used as surrogate marker for steroid response. In acute exacerbation, steroids improve symptoms and lung functions. Inhaled steroids have fewer adverse effects compared with oral agents. Although effective, these agents improve expiratory flows less effectively than oral preparations, even at high doses. These agents may be beneficial in slowing rate of progression in a subset of patients with COPD who have rapid decline.

Fluticasone (Flovent)

Has extremely potent vasoconstrictive and anti-inflammatory activity. Has a weak HPA axis inhibitory potency when applied topically. Effectiveness is not established.

·                                 Dosing

·                                 Interactions

·                                 Contraindications

·                                 Precautions

Adult

Initial: 250-500 mcg bid
Previous therapy:
Bronchodilator alone: 88 mcg bid; may titrate to 440 mcg bid prn
Inhaled corticosteroids: 88-220 mcg bid; may titrate to 440 mcg bid prn
Oral steroids: 880 mcg bid; not to exceed 880 mcg bid

Pediatric

Not established

Budesonide (Pulmicort Turbuhaler)

Has extremely potent vasoconstrictive and anti-inflammatory activity. Has a weak HPA axis inhibitory potency when applied topically. Effectiveness is not established.

·                                 Dosing

·                                 Interactions

·                                 Contraindications

·                                 Precautions

Adult

Previous therapy:
Bronchodilator alone: 200-400 mcg bid; may titrate to 400 mcg bid prn
Inhaled corticosteroids: 200-400 mcg bid; may titrate to 800 mcg bid prn
Oral steroids: 400-800 mcg bid; may titrate to 800 mcg bid

Pediatric

Not established

Prednisone (Sterapred)

Conduct steroid trial to identify responders. Start corticosteroid therapy at 0.5-1 mg/kg of prednisone daily for 2-3 wk. If the FEV₁ increases by 20% or more, taper dose to the minimum to maintain improvement.

·                                 Dosing

·                                 Interactions

·                                 Contraindications

·                                 Precautions

Adult

0.5-1 mg/kg/d PO qd, gradually taper to minimum 10-20 mg/d, the dose that maintains improvement is continued long-term

Pediatric

Not established

Smoking cessation therapies

Work best when used in conjunction with a support program, such as counseling, group therapy, or behavioral therapy. Nicotine replacements may be used to decrease physical withdrawal symptoms.

Antidepressants (eg, bupropion) are used as a nonnicotine aid to smoking cessation. One study demonstrated 23% sustained cessation with bupropion tablets at 1 year, compared to a 12% sustained cessation with placebo. Bupropion also may be effective in patients for whom nicotine replacement therapy is ineffective.

The most recent drug to receive approval for smoking cessation is varenicline (Chantix), a partial agonist selective for alpha4, beta2 nicotinic acetylcholine receptors.

Nicotine patches (Habitrol, NicoDerm CQ) or nicotine polacrilex (Nicorette)

Nicotine patches: Individuals who smoke >1 pack/d initially need a 21-mg patch, followed by 14- and 7-mg patches.
Nicotine polacrilex: Nicotine is absorbed through the oral mucosa. Is absorbed quickly and closely approximates time course of plasma nicotine levels observed after cigarette smoking.
Available as 2- or 4-mg gum in a box containing 96 pieces. Careful adherence to chewing instructions is important for effective use. Manufacturer recommends that the gum not be used l>6 mo.
An individual who smokes 1 pack/d should use 4-mg pieces. The 2-mg pieces are to be used by individuals who smoke <1 pack/d. Instruct the patient to chew hourly and for initial cravings for 2 wk, then gradually reduce amount chewed over 3 mo.

·                                 Dosing

·                                 Interactions

·                                 Contraindications

·                                 Precautions

Adult

Habitrol/NicoDerm CQ: One 21-mg patch qd for 3-4 wk, then one 14-mg patch qd for 3-4 wk, followed by one 7-mg patch qd for 3-4 wk
Nicotrol: One 15-mg patch qd for 6 wk, then one 10-mg patch qd for 2 wk, followed by one 5-mg patch qd for 2 wk
Nicotine polacrilex: 1 piece of gum (2 mg) per h as needed to abstain from smoking; not to exceed 30 mg/d

Pediatric

Not established

Bupropion (Zyban)

Used in conjunction with a support group and/or behavioral counseling. Inhibits neuronal dopamine reuptake in addition to being a weak blocker of serotonin and norepinephrine reuptake.

·                                 Dosing

·                                 Interactions

·                                 Contraindications

·                                 Precautions

Adult

150-mg tab qd for 3 d, then increase to 150 mg bid with at least 8 h between each dose for 7-12 wk

Pediatric

Not established

Varenicline (Chantix)

Partial agonist selective for alpha4, beta2 nicotinic acetylcholine receptors. Action is thought to be the result of activity at a nicotinic receptor subtype, where its binding produces agonist activity while simultaneously preventing nicotine binding. Agonistic activity is significantly lower than nicotine. Also elicits moderate affinity for 5-HT3 receptors. Maximum plasma concentrations occur within 3-4 h after oral administration. Following regular dosing, steady state is reached within 4 d.

·                                 Dosing

·                                 Interactions

·                                 Contraindications

·                                 Precautions

Adult

Initiate 1 wk before date chosen to stop smoking
Days 1-3: 0.5 mg PO qd pc
Days 4-7: 0.5 mg PO bid pc
Day 8 to end of treatment: 1 mg PO bid pc
Continue treatment for 12 wk; if successfully stopped smoking at end of 12 wk, an additional course of 12 wk treatment is recommended; take after meals with full glass of water
Severe renal impairment (ie, CrCl <30 mL/min): Not to exceed 0.5 mg PO bid
ESRD with hemodialysis: Not to exceed 0.5 mg PO qd

Pediatric

<18 years: Not established

Beta-adrenergic agonist and anticholinergic agent combinations

Combine the benefits of the rapid onset of a beta-adrenergic agonist with the prolonged action of an anticholinergic agent.

Ipratropium and albuterol (DuoNeb)

Ipratropium is chemically related to atropine, Has antisecretory properties, and, when applied locally, inhibits secretions from serous and seromucous glands lining the nasal mucosa.
Albuterol is a beta-agonist for bronchospasm refractory to epinephrine. Relaxes bronchial smooth muscle by action on beta2-receptors with little effect on cardiac muscle contractility.

·                                 Dosing

·                                 Interactions

·                                 Contraindications

·                                 Precautions

Adult

3-mL vial administered qid via nebulization with up to 2 additional 3-mL doses allowed per d, if needed

Pediatric

Not established

Antibiotics

Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the context of the clinical setting.

Cefuroxime (Zinacef)

Second-generation cephalosporin. Maintains gram-positive activity that first-generation cephalosporins have. Adds activity against P mirabilis, H influenzae, E coli, K pneumoniae, and M catarrhalis. 
Condition of patient, severity of infection, and susceptibility of microorganism determines proper dose and route of administration.

·                                 Dosing

·                                 Interactions

·                                 Contraindications

·                                 Precautions

Adult

2 g IV q6-8h

Pediatric

80-160 mg/kg/d IV divided q4-6h

Azithromycin (Zithromax)

Replacing erythromycin as therapy for community-acquired pneumonia. Cover most potential etiologic agents, including Mycoplasma. Newer macrolides offer decreased GI upset and potential for improved compliance through reduced dosing frequency. Improved action against H influenzae.

·                                 Dosing

·                                 Interactions

·                                 Contraindications

·                                 Precautions

Adult

Day 1: 500 mg PO
Days 2-5: 250 mg PO qd
Alternatively, administer 500 mg IV qd

Pediatric

<6 months: Not established
> 6 months:
Day 1: 10 mg/kg PO once; not to exceed 500 mg/d
Days 2-5: 5 mg/kg PO qd; not to exceed 250 mg/d

Clarithromycin (Biaxin)

Inhibits bacterial growth, possibly by blocking dissociation of peptidyl tRNA from ribosomes, causing RNA-dependent protein synthesis to arrest. Initial therapy in otherwise uncomplicated pneumonia.

·                                 Dosing

·                                 Interactions

·                                 Contraindications

·                                 Precautions

Adult

500 mg PO bid for 10 d

Pediatric

Not established

Follow-up

Further Inpatient Care

• Acute exacerbation of COPD
• Acute exacerbation of chronic obstructive pulmonary disease (COPD) is one of the major reasons for hospital admission in the United States.
• Because of the lack of clinical studies, the general consensus supports the need for hospitalization of patients who develop severe respiratory dysfunction, disease progression, and other comorbid conditions (eg, pneumonia, poor response to outpatient management).
• The purpose of hospitalization is to manage the patient's acute decompensation and to prevent further deterioration.
• Pharmacotherapy of COPD exacerbations
• Physicians recommend a stepwise approach to drug therapy that takes into consideration the causes and complications related to the exacerbation, the degree of reversible bronchospasm, recent drug use, and contraindications to treatment. Sedation and pain management must be provided, despite a potential for respiratory depression, to ensure patient comfort and safety.
• Patients with exacerbations respond to inhaled beta2 agonists and anticholinergic aerosols. Treatment is initiated with an inhaled beta2 agonist delivered via a spacer or nebulizer; inhaled ipratropium bromide usually is added. The combination therapy may act synergistically and may allow using lower dosages of beta agonists. The efficacy of theophylline or intravenous aminophylline is not definitively established, and theophylline and intravenous aminophylline may cause toxicity.
• Corticosteroids generally are recommended and may be used intravenously for a short period. When a response occurs, lower the dosage. Careful observation and spirometric evaluation are needed to prove the continuing benefit of steroids after a course of 1-2 weeks.
• Antibiotic therapy
• Antibiotics should be prescribed in a COPD exacerbation if the patient shows clinical signs of infection, such as fever, leukocytosis, and/or pulmonary infiltrate on chest radiographs. The antibiotic choice should depend on the clinical picture and local resistance patterns.
• The risk stratification scheme for antibiotic selection is recommended as follows: treat low-risk patients with amoxicillin, trimethoprim/sulfamethoxazole, or doxycycline. Treat high-risk patients, those who had multiple exacerbations in the past, and/or those with underlying cardiopulmonary dysfunction with a new-generation macrolide, a second-generation cephalosporin, or a fluoroquinolone.
• Intensive care admission: Indications for intensive care admission are confusion, lethargy, respiratory muscle fatigue, worsening hypoxemia, respiratory acidosis (ie, pH <7.30), or when a patient requires invasive or noninvasive mechanical ventilation.
• Assisted ventilation
• Progressive airflow obstruction may impair oxygenation and/or ventilation to the degree that the patient requires assisted ventilation.
• The general guidelines for determining the ideal time to initiate ventilatory support are (1) patients who have experienced progressive worsening of respiratory acidosis and/or altered mental status and (2) clinically significant hypoxemia despite supplemental oxygen.
• Patients may be treated with noninvasive mask ventilation or translaryngeal intubation and mechanical ventilation. Following noninvasive ventilation, provide adequate patient supervision and ensure patient's mental alertness and tolerance of appliances. Hemodynamic instability, difficulty with clearing of secretions, and copious secretions are contraindications to noninvasive assisted ventilation. See Noninvasive positive-pressure ventilation in Medical Care.
• The main goal of assisted positive pressure ventilation in acute respiratory failure complicating COPD is to rest the ventilatory muscles and restore gas exchange. Major risks are ventilator-associated pneumonia, barotrauma, and laryngotracheal complications associated with intubation.

Further Outpatient Care

• Pulmonary rehabilitation
• Many patients with chronic obstructive pulmonary disease (COPD) are unable to enjoy life to the fullest because of shortness of breath, physical limitations, and inactivity.
• Pulmonary rehabilitation encompasses an array of therapeutic modalities designed to improve the patient's quality of life by decreasing airflow limitation, preventing secondary medical complications, and alleviating respiratory symptoms.
• The 3 major goals of the comprehensive management of COPD are the following:
• Lessen airflow limitation
• Prevent and treat secondary medical complications (eg, hypoxemia, infection)
• Decrease respiratory symptoms and improve quality of life
• Pulmonary rehabilitation, a multidisciplinary team approach
• Successful implementation of a pulmonary rehabilitation program usually requires a team approach, with individual components provided by health care professionals who have experience in managing COPD (eg, physician, dietitian, nurse, respiratory therapist, exercise physiologist, physical therapist, occupational therapist, recreational therapist, cardiorespiratory technician, pharmacist, psychosocial professionals).
• This multidisciplinary approach emphasizes patient and family education, smoking cessation, medical management (eg, oxygen, immunization), respiratory and chest physiotherapy, physical therapy with bronchopulmonary hygiene, exercise, vocational rehabilitation, and psychosocial support.
• Benefits of pulmonary rehabilitation: As a result of rehabilitation, improvements occur in the objective measures of quality of life, well being, and health status, including a reduction in respiratory symptoms and an increase in exercise tolerance and functional activities (eg, walking, less anxiety and depression, increased feelings of control, self-esteem). An observational study has also shown that pulmonary rehabilitation improves the BODE score in patients with COPD and is associated with better outcomes.⁴⁰Pulmonary rehabilitation also results in substantial savings in healthcare costs by reducing use of hospital and medical resources.
• Components of pulmonary rehabilitation
• Pulmonary rehabilitation programs usually are conducted in an outpatient setting. A rehabilitation program may include a number of components and should be tailored to the needs of the individual patient. Provide all patients who complete the program with guidelines for continuing at home.
• Education is key to comprehensive pulmonary rehabilitation. The educational component prepares the patient and families to be actively involved in providing care. This reliance on patients to assume charge of their care is known as collaborative self-management.
• Exercise training is a mandatory component of pulmonary rehabilitation. Patients with COPD should perform aerobic lower extremity endurance exercises regularly to enhance performance of daily activities and reduce dyspnea. Upper extremity exercise training improves dyspnea and allows increased activities of daily living requiring the use of upper extremities.
• Breathing retraining techniques (eg, diaphragmatic, pursed lip breathing) may improve the ventilatory pattern and prevent dynamic airway compression.

Prognosis

See Staging.

Patient Education

• For excellent patient education resources, visit eMedicine's Lung and Airway Center. Also, see eMedicine's patient education articles Chronic Obstructive Pulmonary Disease (COPD), Cigarette Smoking, Asthma, and Emphysema.
• The Medscape COPD Resource Center may be helpful.

Miscellaneous

Medicolegal Pitfalls

• Differentiating chronic obstructive pulmonary disease (COPD) from asthma is difficult because of overlap in the pathophysiology, clinical presentation, pulmonary function test results, and treatment. The approach to treatment and prognosis differ because of relative importance of anticholinergic versus beta2-agonist therapy and the use of corticosteroids or other inflammatory agents.
• Although exacerbations are an important event in the natural history of patients who have COPD, limited information is available on the frequency of exacerbations and their effect on the course of COPD. Many patients have subclinical exacerbations that should be treated aggressively to prevent complications.
• Controversy exists about which patients should receive a trial of systemic or inhaled corticosteroids. Although a small fraction improves markedly, no screening test identifies the responders and the characteristics that constitute improvement are unclear.
• Alpha1-antitrypsin (AAT) replacement therapy for those who are deficient is controversial. Long-term studies are underway to determine the efficacy of this treatment. Researchers have yet to determine the optimal dose and dosing regimen.
• Noninvasive ventilation to provide intermittent respiratory muscle rest is beneficial in a select group of patients but is considered controversial and requires further clinical studies.
• More information is required to determine whether pulmonary rehabilitation, lung volume reduction surgery, and/or lung transplantation represent cost effective interventions.
• Although preliminary studies show that inhaled corticosteroids may reduce progression of airflow obstruction, this should be confirmed with large prospective studies.

Special Concerns

• Air travel
• Many commercial planes fly at altitudes of 30,000-40,000 feet. However, the cabin is pressurized to an altitude of 5000-8000 feet. At these altitudes, atmospheric partial pressure of oxygen (PO₂) is 132-109 mm Hg, compared to 159 mm Hg at sea level.
• Acute reduction in PO₂ stimulates peripheral chemoreceptors, which results in hyperventilation. A prediction equation used to estimate PaO₂ at 8000 feet (2440 m) is as follows:

PaO₂ = 22.8-2.74X + 0.68Y
X = altitude Y = arterial PO₂ at sea level

• A predicted PaO₂ of 50 mm Hg or less at an altitude of 8000 feet is an indication for supplemental oxygen. Arrange supplemental oxygen prior to the flight directly through the airline or through the airline agent (at an extra expense).
• Sleep and COPD
• Patients with COPD may develop substantial decreases in nocturnal PaO₂ during all phases of sleep, but particularly during the rapid eye movement phase. These episodes initially are associated with a rise in pulmonary arterial pressures and disturbance in sleep architecture, but they may develop into pulmonary arterial hypertension and cor pulmonale if hypoxemia remains untreated.
• Prescribe oxygen for patients who have daytime PaO₂ greater than 60 mm Hg but demonstrate substantial nocturnal hypoxemia.